AB0382 COMPARISON OF ADVERSE EVENTS (AEs) RELATED TO MAJOR ANTI-RHEUMATIC DRUGS, REPORTED TO THE OFFICIAL JAPANESE ADVERSE DRUG EVENT REPORT DATABASE (JADER)
Authors: N. Tsuda, S. Inokuma, H. Noguchi, M. Yamaji, T. Harada, M. Misaki, Y. Masui, T. Kano
Journal: Annals of the Rheumatic Diseases (2022)

Background Currently, many disease-modifying anti-rheumatic drugs (DMARDs) are available for the treatment of rheumatoid arthritis (RA). Among them, methotrexate (MTX), biologic DMARDs (bDMARDs) and Janus kinase inhibitors (JAKi) are the major options. AEs related to these are major concerns. In Japan, the AEs data spontaneously reported to and summarized by Pharmaceuticals and Medical Devices Agency (PMDA) are freely accessible. Objectives The major AEs relating to MTX, bDMARDs, and JAKi observed in the real world were compared. Methods The number of AEs listed by JADER from 2014 to 2020 was collected. The AEs were classified by System Organ Class (SOC) of Medical Dictionary for Regulatory Activities (MedDRA) and compared using the chi-square test. The bDMARDs included were etanercept (ETN), adalimumab (ADA), golimumab (GOL), tocilizumab (TCZ), and abatacept (ABT), and JAKi was tofacitinib (TOF) and baricitinib (BAR). Results The total number of AEs was 27,604. The number was significantly increasing in total and MTX, GOL, TOF during these years, although the number of cases that have each DMARD is not known in this study. The proportion of SOCs among each DMARD was similar throughout the period. The most frequent was infections/infestations in all DMARDs except for MTX, in which neoplasms were the most. The primary cause of infection was bacterial, including pneumonia. Varicella-zoster virus infection in JAKi, and tuberculosis in ADA and GOL were conspicuous. Neoplasms were the second major in many DMARDs. Lymphoproliferative disorders were most common in MTX-related neoplasms, whereas solid tumors were more in other DMARDs like ABT or BAR. Other SOCs include all other categories such as the musculoskeletal, nervous system, cardiac, and vascular disorders. Among them, major adverse cardiovascular events (MACE, including cardiovascular death, myocardial infarction and stroke) and venous thromboembolism (VTE) were both reported in small numbers. However, more MACE was noted in BAR and GOL, and more VTE was in BAR and TOF compared to other DMARDs. Conclusion The number of AEs cases related to DMARDs was increasing. Significant difference among AEs related to DMARDs was noted in the JADER database, especially regarding MTX and JAKi. References [1]S. Inokuma. Expert Open Drug Saf. 2021 Nov 11. Online ahead of print. Table 1. Total case numbers and proportion of adverse events related to each DMARD. DMARDs (year of launch) Total MTX (1999) ETN (2005) ADA (2008) GOL (2011) TCZ (2008) ABT (2010) TOF (2013) BAR (2017) Number of AEs 27604 11636 2974 1959 1302 4245 1709 3065 714 Blood/lymphatic system disorders 5.8 9.9 2.0 3.2 2.6 4.0 0.9 2.8 3.5 Gastrointestinal disorders 5.0 4.1 3.4 7.5 5.9 7.7 3.9 5.2 4.2 General disorders/administration site reactions 4.6 3.2 11.3 4.1 2.2 3.0 4.0 7.6 2.5 Infections/infestations 28.0 20.3 21.3 32.2 34.2 36.5 37.1 37.0 49.2 Pneumonia (bacterial) 6.6 4.0 6.1 5.2 10.9 7.7 12.5 9.4 15.1 Other bacterial infection 9.1 5.9 5.6 12.3 9.5 17.6 9.1 9.8 10.6 Herpes zoster 2.1 1.1 0.4 1.4 1.2 1.0 1.2 8.2 11.2 Tuberculosis 1.4 0.9 1.9 6.0 3.5 0.6 0.6 0.3 1.0 Investigations 5.0 4.9 5.5 2.3 2.6 5.7 2.2 8.3 2.8 Neoplasms benign, malignant, unspecified 21.1 34.8 11.0 13.5 12.7 7.4 15.6 10.8 15.4 Lymphoproliferative diseases 14.3 29.8 2.8 4.1 4.0 2.2 4.5 2.1 2.2 Solid tumors 5.6 3.8 7.3 7.8 7.5 4.0 9.9 7.3 10.5 Respiratory, thoracic, mediastinal disorders 7.1 6.8 8.3 8.4 9.5 6.5 7.4 6.2 6.7 Other System Organ Class 23.3 15.9 37.3 28.8 30.2 29.2 28.9 22.2 15.7 Major adverse cardiovascular events 1.1 0.4 1.1 1.6 2.5 1.5 1.6 1.3 2.9 Venous thromboembolism 0.4 0.1 0.4 0.5 0.6 0.3 0.2 1.1 1.4 Background colors indicate: comparing to the total cases, higher with p&lt;0.05 , light pink; higher with p&lt;0.00001 , dark pink; higher with p&lt;1E-10 , red. Lower with p&lt;0.05 , light blue; lower with p&lt;0.00001 , blue; lower with p&lt;1E-10 , dark blue, using chi-square test. Yellow indicates System Organ Classes. Figure 1. Total number of adverse events reported from 2014 to 2020. Linear regression is shown only for DMARDs with increasing numbers of AEs. Disclosure of Interests None declared